CN101007789A - Substituted quinary aza heterocyclic salt compound and its uses in therapeutic protein aging-related disease - Google Patents

Substituted quinary aza heterocyclic salt compound and its uses in therapeutic protein aging-related disease Download PDF

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CN101007789A
CN101007789A CNA2006100023916A CN200610002391A CN101007789A CN 101007789 A CN101007789 A CN 101007789A CN A2006100023916 A CNA2006100023916 A CN A2006100023916A CN 200610002391 A CN200610002391 A CN 200610002391A CN 101007789 A CN101007789 A CN 101007789A
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compound
formula
branched
treating
methyl
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CN101007789B (en
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李松
崔浩
肖军海
钟武
王莉莉
程罡
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BEIJING MUOLIKE SCIENCE AND TECHNOLOGY Co Ltd
Beijing Molecule Science and Technology Co Ltd
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BEIJING MUOLIKE SCIENCE AND TECHNOLOGY Co Ltd
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Priority to CN201410332231.2A priority patent/CN104151261B/en
Priority to US12/223,236 priority patent/US7799813B2/en
Priority to PCT/CN2007/000319 priority patent/WO2007085203A1/en
Priority to BRPI0706883-2A priority patent/BRPI0706883A2/en
Priority to AU2007209704A priority patent/AU2007209704B2/en
Priority to RU2008134899/04A priority patent/RU2444517C2/en
Priority to KR1020087020808A priority patent/KR101229282B1/en
Priority to CA2640396A priority patent/CA2640396C/en
Priority to EP07710857A priority patent/EP1985296B1/en
Priority to JP2008551634A priority patent/JP5797370B2/en
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Abstract

The invention relates to a five-membered ring heterocyclic compound expressed in general formula I and its medical salt and hydrated, and the definition of each group is expressed in instruction manual. The invention also relates to the medical compound comprising said compound or its medical salt or hydrate, and the application of said compounds. Said application comprises: (1) intensifying skin elasticity or reducing skin furrow, (2) treating diabetes. (3) treating or releasing the diabetes sequelae, (4) treating or releasing kidney injury, (5) treating or releasing blood vessel injury, (6) treating or releasing high blood pressure, (7) treating or releasing retina pathology, (8) treating or releasing crystalline injury, (9) treating or releasing cataract, (10) treating or releasing peripheral nervous disease, (11) treating or releasing ostarthritis.

Description

The purposes of new substituted penta azacyclo salt compounds and treatment diseases relative to protein aging thereof
Technical field
The present invention relates to the substituted penta azacyclo salt compounds, its preparation method, the pharmaceutical composition and the purposes of described compound in prevention or treatment and AGEs diseases associated or symptom that contain them, comprise that (i) increases skin elasticity or reduce wrinkle of skin, (ii) treat diabetes, the (iii) treatment or the sequela of diabetes-alleviating, (iv) treat or the alleviation kidney injury, (v) treatment or alleviating vascular damage, (vi) treat or alleviation hypertension, (vii) treat or the relieving retina pathology, (viii) treatment or the damage of alleviation crystallin, (ix) treatment or alleviation cataract, (x) treatment or alleviation peripheral neuropathy and (xi) treatment or relief from osteoarthritis.
Background technology
There is reaction between known sugars and the albumen.As far back as 1912, Maillard found glucose and other reducing sugar and amino acid reaction, reset through a series of dehydrogenation and had formed stable brown pigment.Discover that further storage and heat food also can produce this pigment that is formed by sugar and polypeptide.The formation of this pigment has reduced proteic biological activity, and relevant application patent can be with reference to US.08/588249.The reducing sugar of this non-enzymatic catalysis and the reaction of free amino acid can form a kind of stable diketo by product, promptly known Amadori product.Particularly the β side chain residue of protoheme surface amino groups acid and glucose response generate protoheme Alc.Such reaction also can take place in other albumen in the body, such as lens, collagen protein and neuroprotein (Advanced Glycosylation; Chemistry, Bilolgy andImplications for Diabetes and Aging, Advances inPharmacology, Vol.23, pp.1-34A cademic Press 1992).
Above-mentioned being reflected at can quicken under the situation that the diabetes glucose level increases to take place, and also above-mentioned reaction can take place under the euglycemia state.The formation of aging course and lipofuscin is closely related simultaneously.Same collagen protein wears out and can simulate with sugar and collagen protein external.The collagen product of glucose induction has been caused the crosslinking reaction between the albumen like this by other albumen capture reaction.This glucose induction crosslinking reaction produced be advanced glycation end products (advancedglycosylation endproducts, AGEs).Known AGEs is relevant with the complication of diabetes, and normal aging course also causes the increase of AGEs.Intravital AGEs is not only because its unusual pathological chemistry structure, but also because it can be by some specific acceptors identification, thereby cause the pathological change that complicated diabetes are relevant with aging.
The methods of treatment that some accumulation aspects by stoping AGEs have been arranged at present.One of them method can be referring to USP4758583, wherein guide's thing aminoguanidine and analogue thereof can stop the formation of AGEs, thereby promptly, also stoped AGEs simultaneously and organized further crosslinked by having stoped glycation product further to transform into AGEs with early stage glycation product reaction.The validity of this method is estimated on the animal model of diabetes and aging rat, also comprises other indexs as great vessels, kidney and europathology aspect simultaneously.People such as Vlassara sum up these data.(Vlassara et al., 1994 Biology ofDiseases, " Pathogenic effects of advanced glycosylation:biochemical, biologic and clinical implications fordiabetes and aging " Laboratory Investigation 70:138-151; Brownlee, 1995, " The pathological implica tions of proteinglycation " Clin.Invest.Med., 18:275-281; And Brownlee, 1995, " Advanced protein glycosylation in diabetes and aging ", Ann.Rev.Med.46:223-34.)
AGEs in the another kind of control tissue has particularly formed in tissue and the method for cumulative AGEs cross-linking products (these cross-linking products cause clinical or subclinical pathological change) is the AGEs cross-linking products that reverse or cracking have formed.People such as Vassan prove that the method for this cracking AGEs is effective (vassan et al., Nature.1996, Vol.382 (18) 275-278).The AGEs crosslinking structure that compound, preparation and the method for announcing in U.S. Pat P5656261 and US08/588249 and US08/848776 can be have in vivo formed with external cracking.Studies show that the cardiovascular disorder that this compounds causes for aging has good effect (Wolffenbuttel et al., 1998, " Breakers of Advanced Glycation End Products RestoresLarge Artery Properites in Experimental Diabetes ", Proc.Nat.Acad.Sci.U.S.A.95:4630-4634).In these researchs, given reversing in diabetes rat AGEs cracking agent 1-3 week of 9 weeks because the Aorta sclerosis that diabetes cause.The parameter of improving has cardiac output, Peripheral resistance, body arterial compliance, aorta input resistance and carotid artery conformability (USP6319934).
Summary of the invention
The objective of the invention is to seek and developmental function in the small molecules cracking agent of AGEs, thereby being used for the AGEs that cracking formed stops protein-crosslinking, and crosslinked albumen carried out cracking, thereby promote proteic metabolism, treatment or prevention owing to AGEs in vivo increase the various pathological changes that cause, comprise and increase skin elasticity or reduce wrinkle of skin, the sequela of treatment diabetes or treatment or diabetes-alleviating, kidney injury, blood vessel injury, hypertension, retinopathy, the crystallin damage, cataract, peripheral neuropathy or osteoarthritis.The glycosylated protein that this protein-crosslinking structure cracking agent of while is acted on is not limited to human body protein, also comprises vegetable-protein or animal proteinum in the farm crop, thereby can expand the fresh-keeping purposes that is used for farm crop vegetable-protein and animal proteinum.
The inventor has been found that the compound of following general formula I can be used for the treatment of and/or prevent the multiple disease that is caused by protein glycosylation.
The inventor finds, has than better AGEs lytic activity of the preferred compound ALT-711 that discloses among the USP5656261 and lower toxicity on the multiple in vitro and in vivo model of compound of Formula I.
Therefore, first aspect present invention relates to the compound of general formula I, or its pharmacologically acceptable salt or hydrate,
Figure A20061000239100081
Wherein:
X is O or S,
Y is O or S,
Q is O or NH,
R 1And R 2Can be identical or different, and be independently selected from hydrogen, C 1～C 4Alkyl, C 2～C 4Thiazolinyl and hydroxyl C 1～C 4Alkyl, perhaps R 1And R 2Link to each other and form aromatic nucleus Ar 2, perhaps five yuan or hexa-atomic cycloaliphatic ring,
R 3Be hydrogen, C 1～C 8Straight chain or branched-chain alkyl, C 2～C 8Straight chain or branched-chain alkenyl, C 3～C 8Cycloalkyl, hydroxyl, C 1～C 4Alkoxyl group, C 1～C 4Alkylamino, itrile group, perhaps trifluoromethyl,
R 4Be hydrogen, C 1～C 8Straight chain or branched-chain alkyl, C 2～C 8Straight chain or branched-chain alkenyl, C 3～C 8Cycloalkyl, perhaps monocycle, dicyclo or trinucleated aromatic carbocyclic or heterocyclic group, wherein each ring is made up of 5～6 annular atomses, comprises 1～6 in the heterocyclic group and is selected from O, the heteroatoms of S and N; Can not have replacement on the ring, can be selected from following substituting group yet and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C by 1-3 1～C 6The straight or branched alkyl, C 2～C 6The straight or branched thiazolinyl, C 1～C 4Alkoxyl group, C 2～C 4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl and amino,
Z -It is acceptable acid group pharmaceutically.
According to an embodiment preferred, the present invention relates to formula I compound, perhaps its pharmaceutical salts or its hydrate
Figure A20061000239100091
Wherein:
X is S,
Y is O or S,
Q is O or NH,
R 1And R 2Can be identical or different, and be independently selected from hydrogen, C 1～C 4Alkyl, C 2～C 4Thiazolinyl and hydroxyl C 1～C 4Alkyl; Perhaps R 1And R 2Link to each other and form aromatic nucleus Ar 2Or five yuan or hexa-atomic cycloaliphatic ring,
R 3Be hydrogen, C 1～C 8Straight chain or branched-chain alkyl, C 2～C 8Straight chain or branched-chain alkenyl, C 3～C 8Cycloalkyl, hydroxyl, C 1～C 4Alkoxyl group, C 1～C 4Alkylamino, itrile group, or trifluoromethyl,
R 4Be hydrogen, C 1～C 8Straight chain or branched-chain alkyl, C 2～C 8Straight chain or branched-chain alkenyl, C 3～C 8Cycloalkyl, perhaps monocycle, dicyclo or trinucleated aromatic carbocyclic or heterocyclic group, wherein each ring is made up of 5～6 annular atomses, comprises 1～6 in the heterocyclic group and is selected from O, the heteroatoms of S and N; Can not have replacement on the ring, can be selected from following substituting group yet and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C by 1-3 1～C 6The straight or branched alkyl, C 2～C 6The straight or branched thiazolinyl, C 1～C 4Alkoxyl group, C 2～C 4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl and amino,
Z -It is acceptable acid group pharmaceutically.
According to a preferred embodiment, the present invention relates to following formula I compound or pharmaceutically acceptable salt thereof or hydrate,
Figure A20061000239100101
Wherein:
X is S,
Y is O,
Q is O,
R 1, R 2, R 3And R 4Definition the same,
Z-is pharmaceutically acceptable acid group, for example F -, Cl -, Br -, I -, methanesulfonate or to the methylsulphonic acid root, wherein preferred Hydrogen bromide root and methanesulfonate.
Compound of the present invention includes but not limited to:
M.p. ℃ of compound chemistry name structure
1 3-carbobenzoxy-(Cbz) methyl-4,5-dimethyl-thiophene
Azoles-3-bromate
Figure A20061000239100111
Oil
2 3-carbobenzoxy-(Cbz) methyl-5-(2-hydroxyl-second
Base)-4-methyl-thiazole-3-bromate
Figure A20061000239100112
Oil
3 3-carbobenzoxy-(Cbz) methyl-4-methyl-thiazole-3-
Bromate
Figure A20061000239100113
217-218
4 3-carbobenzoxy-(Cbz) methyl-4,5,6, the 7-tetrahydrochysene-
Benzothiazole-3-bromate
Figure A20061000239100114
160-166
5 3-carboxymethyl-4-methyl-thiazole-3-bromate
Figure A20061000239100115
223-230
Or their pharmaceutical salts or hydrate.
More preferably 3-carbobenzoxy-(Cbz) methyl-4-methyl-thiazole-3-bromate wherein.
According to the present invention, the pharmacologically acceptable salt of The compounds of this invention comprises its inorganic acid salt or organic acid salt, includes but not limited to: hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, oxalate, pivalate, adipate, alginate, lactic acid salt, Citrate trianion, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, mesylate, esilate, benzene sulfonate, tosilate and embonate.
The present invention relates to the method for preparing compound of Formula I or its pharmaceutical salts or its hydrate on the other hand, and it comprises:
A) with following formula thiocarbamide or urea
Figure A20061000239100121
Ketone with formula II
Figure A20061000239100122
R wherein 1And R 2Definition with the definition in the top formula I compound,
Reaction obtains the formula III compound under halogen catalysis, or reacts under halogen catalysis according to document (J.Amer.Chem.Soc., 1949,71,4007) and to obtain the formula III compound,
Figure A20061000239100123
R wherein 1, R 2With the definition of X with the definition in the top formula I compound,
B) formula III compound and Isopentyl nitrite reaction are obtained formula IV compound
Figure A20061000239100124
R wherein 1, R 2It is the same with the definition of X,
C) with the compound of formula IV compound and formula V
Figure A20061000239100125
R wherein 3, Y, Q and R 4Definition with the definition in the top compound of Formula I, X ' is a leavings group, for example F, Cl, Br, I, methanesulfonate are closed or the methylsulphonic acid root are closed, reaction obtains compound of Formula I
Figure A20061000239100131
R wherein 1, R 2, R 3, X, Y, Q, R 4The same with the definition of Z.
Randomly, further hydrolysis R wherein 4The compound of Formula I that is not H obtains formula Ia compound:
Figure A20061000239100132
R wherein 1, R 2, R 3, X, Y, the definition of Q and Z is the same,
Wherein Q be 0 formula Ia compound optional again with C 1～C 8The straight or branched alkyl alcohol, C 2～C 8Straight chain or branched-chain alkenyl alcohol, C 3～C 8Cycloalkyl alcohol, or aromatic alcohol carries out the condensation dehydration reaction, obtains various esters.
As required, resulting compound can change another kind of salt into by a kind of salt according to method known per se.
According to a specific embodiment, compound of the present invention can prepare by following reaction scheme:
Reaction scheme I:
Figure A20061000239100141
It comprises makes formula IV compound:
Wherein, X is O or S,
R 1And R 2Can be identical or different, and be independently selected from hydrogen, C 1～C 4Alkyl and C 2～C 4Thiazolinyl; Perhaps R 1And R 2Link to each other and form aromatic nucleus Ar 2,
Compound reaction with formula Va
Figure A20061000239100143
Wherein
Y is O or S,
Q is O or NH
R 3Be hydrogen, C 1～C 8Straight chain or branched-chain alkyl, C 2～C 8Straight chain or branched-chain alkenyl, C 3～C 8Cycloalkyl, hydroxyl, C 1～C 4Alkoxyl group, C 1～C 4Alkylamino, itrile group, or trifluoromethyl,
R 4Be C 1～C 8Straight chain or branched-chain alkyl, C 2～C 8Straight chain or branched-chain alkenyl, C 3～C 8Cycloalkyl, perhaps monocycle, dicyclo or trinucleated aromatic carbocyclic or heterocyclic group, wherein each ring is made up of 5～6 annular atomses, comprises 1～6 in the heterocyclic group and is selected from O, the heteroatoms of S and N; Can not have replacement on the ring, can be selected from following substituting group yet and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C by 1-3 1～C 6The straight or branched alkyl, C 2～C 6The straight or branched thiazolinyl, C 1～C 4Alkoxyl group, C 2～C 4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl and amino,
Obtain compound of Formula I
Figure A20061000239100151
X wherein, Y, Q, R 1, R 2, R 3And R 4Definition the same,
Z -Be Br -
In the superincumbent reaction scheme, being reflected at that solvent such as ethanol or acetonitrile or butanone exist down or having a kind ofly when being liquid not under the situation of solubilizing agent when two kinds of raw materials of formula IV compound and formula Va compound in 80 ℃～100 ℃, carried out in nitrogen 5～96 hours.
The product that reaction obtains can leave standstill crystallization, and recrystallization or use silica gel column chromatography are purified again.Here employed silica gel can be conventional silica gel for chromatography, granularity 10～40um, and eluent is formulated by single or multiple solvent, is preferably pressed the mixed solvent of different ratios preparation by methylene dichloride and methyl alcohol.Obtain formula I compound of the present invention behind the purifying.
The reaction conditions and the product postprocessing of reacting between formula IV compound and other formula V compound are similar to the above.
Employed formula IV compound is known in the above-mentioned reaction scheme, perhaps can adopt multiple method known per se synthetic, for example reaction scheme II.
Reaction scheme II:
Figure A20061000239100152
R wherein 1, R 2Definition cotype I compound with X.
The compound of formula II and urea or thiocarbamide are reacted under the effect of iodine obtain the formula III compound, in anhydrous tetrahydro furan, handle deaminize then, obtain formula IV compound with Isopentyl nitrite.Can adopt the method purifying formula IV compound of molecular distillation or silica gel column chromatography, here employed silica gel can be conventional silica gel for chromatography, granularity 10～40um, eluent is formulated by single or multiple solvent, is preferably pressed the mixed solvent of different ratios preparation by ethyl acetate and hexanaphthene.
Employed formula Va compound is known in reaction scheme I, perhaps can adopt method known per se synthetic.For example, can synthesize in accordance with the following methods:
Figure A20061000239100161
Adopt cupric bromide or bromine or NBS that the bromo that the compound of formula VII carries out the α position is obtained formula Va compound.The mode of the purifying formula Va compound that can adopt is the method for molecular distillation or chromatography.Here employed silica gel can be conventional silica gel for chromatography, granularity 10～40um, and eluent is formulated by single or multiple solvent, is preferably pressed the mixed solvent of different ratios preparation by ethyl acetate and hexanaphthene.Formula Va compound must purifying to remove a spot of α position two bromo-derivatives.
Randomly, R wherein 4Be not H compound of Formula I further hydrolysis to obtain the compound of formula Ia:
Figure A20061000239100171
R wherein 1, R 2, R 3, X, Y, the definition of Q and Z is the same,
Hydrolysis can be carried out according to the conventional procedure of this area, for example carries out under the katalysis of acid or alkali.
Wherein Q is that the compound of the formula Ia of O can be again and various C 1～C 8The straight or branched alkyl alcohol, C 2～C 8Straight chain or branched-chain alkenyl alcohol, C 3～C 8Cycloalkyl alcohol, or aromatic alcohol carries out the condensation dehydration reaction, obtains various esters.
Work as R 3When being not hydrogen, compound of Formula I can be steric isomer.The steric isomer that the present invention may relate to can adopt asymmetric synthesis to obtain single optically active isomer.But the fractionation to racemic modification is the main means that obtain optical pure compound.Method for splitting mainly contains following four kinds: crystallization process, chromatography, KINETIC METHOD and enzyme process.Fractionation for the compound raceme that the present invention relates to, preferably have the crystallization process of practical value: in the solution of raceme in the mixed solvent of water, organic solvent or water and organic solvent formation, add a kind of chiral separation agent, form diastereomer, utilize diastereomer in solvent different solubility and one of them is preferentially separated out.Preferred chiral acid resolving agent can be a tartrate, and mandelic acid, camphorsulfonic acid etc., chiral base resolving agent can be for example α-Ben Yian, various chirality alkaloids etc.And chromatography mainly uses the HPLC chiral column to separate the compound that obtains single optical purity.
The present invention relates to pharmaceutical composition on the other hand, and it comprises compound or its pharmaceutical salts or its hydrate of at least a general formula I, and pharmaceutical carrier or vehicle.Described pharmaceutical composition can be prepared into various forms according to different way of administration.The mentioned compound of the present invention also can be prepared to various pharmacologically acceptable salts.
Pharmaceutical composition of the present invention comprises formula I compound or pharmaceutically acceptable salt thereof of the present invention or hydrate and one or more the suitable pharmaceutically acceptable carrier or vehicle of effective dose.Here pharmaceutical carrier or vehicle include but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum albumin, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.
Another aspect of the present invention relates to the purposes that at least a formula I compound or its pharmaceutical salts or its hydrate are used to prepare the medicine that prevents and/or treats the various diseases that protein glycosylation causes.
The invention still further relates to the method that prevents and/or treats the various diseases that protein glycosylation causes, it comprises needs the above-mentioned patient who prevents and/or treats with preventing and/or treating at least a formula I compound of significant quantity or its pharmaceutical salts or its hydrate.
The compounds of this invention is the potent crosslinking protein cracking agent of a class, compare with ALT-711, The compounds of this invention has quite or the better ability of cracking glycosylated protein, therefore can be used for but be not limited to (i) increasing skin elasticity or reducing wrinkle of skin, (ii) treat diabetes, the (iii) treatment or the sequela of diabetes-alleviating, (iv) treat or the alleviation kidney injury, (v) treatment or alleviating vascular damage, (vi) treat or alleviation hypertension, (vii) treat or the relieving retina pathology, (viii) treatment or the damage of alleviation crystallin, (ix) treatment or alleviation cataract, (x) treatment or alleviation peripheral neuropathy, (xi) treatment or relief from osteoarthritis.
The glycosylated protein that compound disclosed in this invention can act on is not limited to human body protein, also comprises vegetable-protein or animal organ's albumen in the farm crop, thereby compound disclosed by the invention or pharmaceutical composition can be used for fresh-keeping purposes.
The compounds of this invention also can expanded application in stoping or reversing because the tooth staining that the non-enzymatic glycosylation in the oral cavity causes.The therapeutic regimen that contains compound of the present invention can change according to related purposes.
The non-enzymatic glycosylation that occurs in the oral cavity can cause tooth staining.At present employed anti-moth erosion agent can be quickened this glycosylation and further cause the painted of tooth.The cationic germicide that has a class to have anti-moth erosion function recently is used for conventional oral cavity and cleans.These cationic antibacterial agent have the A Laixi fourth, cetyl pyridinium oxymuriate or the like.And these preparations can quicken a step Maillard reaction crucial in the glycosylation, and then painted (Nordbo, J.Dent.Re s., the 58:1429 (1979)) of acceleration tooth.And be reported in that observation in vitro has arrived Tubulicid and benzalkonium chloride can catalysis glycosylation (brownization reaction).Because the Maillard reaction, Tubulicid adds the formation of having quickened pigment in sugar and the amino acid whose mixture.
For these reasons, compound involved in the present invention and pharmaceutical composition thereof can be used for the oral cavity.Additive in oral cavity scavenging solution and the toothpaste.
In the such use of relevant The compounds of this invention, can adopt the appropriate form of nontoxic and pharmaceutically acceptable carrier to be applied in Jiekouye gargle and the toothpaste.
The pharmaceutical composition that comprises The compounds of this invention can be used with following any-mode: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer such as subcutaneous, vein, intramuscular, intraperitoneal, in the sheath, in the ventricle, breastbone interior and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenously or topical mode.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents, perfume compound or tinting material in the above oral preparations form.
When local medication, particularly treat local external application easy to reach and suffer from face or organ, during as eyes, skin or lower intestinal tract, can The compounds of this invention be made different local application's dosage forms according to different trouble faces or organ, specify as follows:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also compound can be made paste form such as vaseline paste.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyethylene oxide, poly(propylene oxide), emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
It may be noted that in addition, the using dosage of The compounds of this invention and using method depend on all multifactor, comprise activity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of the compound of patient's age, body weight, sex, natural health situation, nutritional status, use.Preferred using dosage is between 0.01～100mg/kg body weight/day, and wherein most preferred dose is in 20-30mg/kg body weight/day scope.
Embodiment
The following examples further illustrate the present invention, and the present invention is not constituted any limitation.
Melting point compound is measured by SRY-1 type fusing point instrument, and temperature is not calibrated. 1H-NMR spectrum is measured by Bruker ARX 400 or US Varian Unity Inova 600 type nuclear magnetic resonance spectrometers, and the FAB mass spectrum is measured by the Zabspect high-resolution mass spectrometer.
Universal method: the logical method of thiazole parent nucleus and the reaction of alpha-brominated ester
Figure A20061000239100201
On the superincumbent reaction scheme, the reaction of thiazole parent nucleus and various alpha-brominated ester cpds is to have a kind of when the liquid not under the situation of solubilizing agent in the presence of solvent such as ethanol or acetonitrile or the butanone or when two kinds of raw materials, in 80 ℃～100 ℃, carried out in the nitrogen 5～96 hours.
The product that reaction obtains can leave standstill crystallization, and recrystallization or use silica gel column chromatography are handled and purified again.The silica gel that uses is conventional silica gel for chromatography, granularity 10～40 μ m, and eluent is formulated by single or multiple solvent, is for example pressed the mixed solvent of different ratios preparation by methylene dichloride and methyl alcohol.Obtain target compound behind the purifying.
Embodiment 1:3-carbobenzoxy-(Cbz) methyl-4,5-dimethyl-thiazole-3-bromate
By above-mentioned universal method, use bromoacetic acid benzyl ester and 4, the 5-dimethylthiazole obtains title compound (0.4g, 26%, oily matter).
MS[M +]＝262.1m/e； 1H-NMR(400MHz，DMSO)δ2.349(s 3H)；2.510(s 3H)；5.273(s 2H)；5.728(s 2H)；7.416-7.427(m 5H)；10.104(s 1H)。
Embodiment 2:3-carbobenzoxy-(Cbz) methyl-5-(2-hydroxyl-ethyl)-4-methyl-thiazole-3-bromate
By universal method, use bromoacetic acid benzyl ester and 4-methyl-5-hydroxy ethylthiazole to be raw material, obtain title compound (0.5g, 28%, oily matter).
MS[M +]＝292.1m/e； 1H-NMR(400MHz，DMSO)δ2.322(s 3H)；3.016(tJ＝5.2Hz 2H)；3.769(tJ＝5.2Hz 2H)；5.213(s 2H)；5.730(s 2H)；7.337-7.356(m 5H)；10.521(dJ＝5.5Hz 1H)。
Embodiment 3:3-carbobenzoxy-(Cbz) methyl-4-methyl-thiazole-3-bromate
By universal method, use bromoacetic acid benzyl ester and 4-methylthiazol, obtain title compound (1.2g, 30%, oily matter).
MS[M +]＝313.9m/e； 1H-NMR(400MHz，CD3OD)δ2.512(s 3H)；5.293(s 2H)；5.600(s 2H)；7.356-7.399(m 5H)；7.991(s1H)。
Embodiment 4:3-carbobenzoxy-(Cbz) methyl-4,5,6,7-tetrahydrochysene-benzothiazole-3-bromate
By universal method, use monobromo-acetic acid benzyl ester and 4,5,6, the 7-tetrahydrochysene-benzothiazole obtains title compound (1.3g, 31%, faint yellow solid, m.p.160-166 ℃).
MS[M +]＝288.0m/e； 1H-NMR(400MHz，DMSO)δ1.798(m 4H)；2.681(m2H)；2.903(tJ＝4.3Hz 2H)；5.269(s 2H)；5.702(s 2H)；7.312-7.423(m 5H)；10.172(s 1H)。
Embodiment 5:3-carboxymethyl-4-methyl-thiazole-3-bromate
To be dissolved in 1N K by 3-carbobenzoxy-(Cbz) methyl-4-methyl-thiazole-3-bromate 1g that embodiment 3 obtains 2CO 3In the aqueous solution, stirring at room 3hr, TLC monitoring reaction.Reaction finishes the back and extracts with chloroform 10ml * 3, and water intaking layer, ice bath drip the 1N HBr aqueous solution down makes solution be acid pH=2, and vaporize water solution is extremely done.Add 20 absolute ethanol washing residues, filter away insolubles; The ethanolic soln evaporate to dryness that obtains obtains the tawny solid, i.e. title compound (700mg, productive rate 50%, m.p.223-230 ℃).
MS[M +]＝158.2m/e； 1H-NMR(400MHz，DMSO)2.3606(dJ＝0.8Hz3H)；5.0936(s 2H)；7.7131(dJ＝1.7Hz 1H)；9.7258(dJ＝2.8Hz1H)。
Embodiment 6: the ELISA shaker test of cracking AGE-BSA-collagen cross-linking structure
Make AGE-BSA and the rat tail collagen protein-crosslinking that is coated on the 96 hole enzyme plates, external preparation AGEs crosslinking structure.Adopt ELISA method assessing compound to the crosslinked splitting action of AGEs.
The 96 hole enzyme plate preparations of tail glue primordial covering:
(body weight 200 ± 20g), tail is got in acute execution to normal Wister rat, carries out with lower tail collagen protein preparation process under 4 ℃.At first, extract tail tendon collagen silk, with the physiological saline washing and remove non-collagen silk tissue, wash 3 times through distilled water again, shred, be soaked in 1 week in 4 ℃ 0.1% Glacial acetic acid, during jolt often.With the centrifugal 30min of 8000g, collect centrifugal supernatant collagen solution at last, protein content is measured in the dilution back.By 96 hole enzyme plates (Costar), 4 ℃, 24h discard coating buffer with the full hole of every hole 70 μ g collagen proteins bag, air-dry under the aseptic condition, preservative film bag quilt, and 4 ℃ of storages are standby.
The AGE-BSA preparation:
(Roch) 50mg/ml and 0.5M glucose are in 0.2MPBS (pH7.4) for bovine serum albumin BSA (V), and under 37 ℃ of aseptic conditions, lucifuge was hatched 3-4 month, and making it form glycosylation BSA is BSA-AGEs.Simultaneously, the BSA with no glucose prepares sugar based BSA.Dialyse in 0.01M PBS (pH7.4) dialyzate then, remove unreacted glucose, fluorescent scanning (Exi/Em (395/460nm)) and SDS-PAGE identify that BSA-AGEs forms, and adopts the Lowery method to carry out protein quantification simultaneously.
The analysis determining method flow process:
Tail glue primordial covering 96 orifice plates are expired in the hole and acid collagen 1h with pH7.4PBS; 37 ℃ of SuperBlock (PIERCE), sealing 1h; PBST (PBS-Tween) washes plate 3 times, vibrates 1 minute at every turn; Dilute AGE-BSA with PBS, add in the capable hole of A, B, C, the D of 96 orifice plates with the AGE-BSA100 μ l that obtains maximum degree of crosslinking concentration, the BSA of same concentrations adds in the capable hole of E, F, G, H, and 1 is listed as in preceding 3 holes PBS as system and reagent blank, under 37 ℃, make it and collagen cross-linking 4h; PBST washes plate 4 times, and 1min at interval vibrates; Test-compound adopts the pH7.4PBS dilution, gets 100 μ l/ holes and is added on crosslinked and each 4 hole, BSA hole of AGE-BSA respectively, and the same manner adds PBS100 μ l/ hole and contrasts as non-cracking, hatches 16h for 37 ℃; PBST washes plate 4 times, and 1min at interval vibrates; Add 37 ℃ of the 80 μ l/ hole anti-BSA antibody of rabbit (1: 500), 50min; PBST washes plate 4 times, and 1min at interval vibrates; Add 37 ℃ of 80 μ l/ hole horseradish peroxidase-labeled goat anti-rabbit iggs (1: 1000), 50min; PBST washes plate 3 times, and 1min at interval vibrates; Add substrate solution TMB (3,3 ', 5,5 '-tetramethyl benzidine) 100 μ l/ pore chamber temperature, black out 20min; Use 2mol/L H 2SO 4Termination reaction; In the 10min, under BOBRAD Mode 1550 plate reading machine 450nm, the OD value is read in the zeroing of plate blank well.
Data analysis:
Average OD value adopts 4 hole mean values.
Proofread and correct the OD mean value in the OD mean value-BSA hole in OD=AGE-BSA hole
Cleavage rate is represented with the percentage that the OD value reduces:
[the OD mean value in (the OD mean value in PBS hole-be subjected to reagent thing hole OD mean value)/PBS hole] * %
According to above-mentioned steps, tested the cleavage rate of test-compound 0.1,0.3, under 1mmol/L or the low concentration, and 0.1 and 1mmol/L concentration under the results are shown in Table 1 (result is the mean value of The selection result more than 3 times):
Table 1:ELISA measures the cleavage rate of compound to the AGE-BSA-collagen cross-linking
Compound Cleavage rate (OD reduction value %)
1(mmol/L) 0.1(mmol/L)
ALT-711 15.2±8.43 13.4±6.41
1 10.81±3.86 9.65±3.55
2 13.25±10.29 13.5±9.53
3 26.46±18.2 16.16±7.07
4 7.17±2.40 8.45±5.35
5 - -

Claims (10)

1. the compound of general formula I, or its pharmacologically acceptable salt or hydrate,
Figure A2006100023910002C1
Wherein:
X is O or S,
Y is O or S,
Q is O or NH,
R 1And R 2Can be identical or different, and be independently selected from hydrogen, C 1～C 4Alkyl, C 2～C 4Thiazolinyl and hydroxyl C 1～C 4Alkyl, perhaps R 1And R 2Link to each other to form aromatic nucleus, perhaps five yuan or hexa-atomic cycloaliphatic ring,
R 3Be hydrogen, C 1～C 8Straight chain or branched-chain alkyl, C 2～C 8Straight chain or branched-chain alkenyl, C 3～C 8Cycloalkyl, hydroxyl, C 1～C 4Alkoxyl group, C 1～C 4Alkylamino, itrile group, or trifluoromethyl,
R 4Be hydrogen, C 1～C 8Straight chain or branched-chain alkyl, C 2～C 8Straight chain or branched-chain alkenyl, C 3～C 8Cycloalkyl, perhaps monocycle, dicyclo or trinucleated aromatic carbocyclic or heterocycle, wherein each ring is made up of 5～6 annular atomses, comprises 1～6 in the heterocyclic group and is selected from O, the heteroatoms of S and N; Can not have replacement on the ring, can be selected from following substituting group yet and replace: halogen, nitro, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, C by 1-3 1～C 6The straight or branched alkyl, C 2～C 6The straight or branched thiazolinyl, C 1～C 4Alkoxyl group, C 2～C 4Alkene oxygen base, phenoxy group, benzyloxy, carboxyl and amino,
Z -It is acceptable acid group pharmaceutically.
2. the compound of claim 1 or its pharmaceutically useful salt or hydrate,
Wherein:
X is S,
Y is O,
Q is O,
R 1, R 2And R 3And R 4Definition with claim 1,
Z -Be halogen acid group F -, Cl -, Br -, I -, perhaps methanesulfonate, to the methylsulphonic acid root, preferred Hydrogen bromide root and methanesulfonate.
3. claim 1 or 2 compound, it is selected from:
3-carbobenzoxy-(Cbz) methyl-4,5-dimethyl-thiazole-3-bromate,
3-carbobenzoxy-(Cbz) methyl-5-(2-hydroxyl-ethyl)-4-methyl-thiazole-3-bromate,
3-carbobenzoxy-(Cbz) methyl-4-methyl-thiazole-3-bromate,
3-carbobenzoxy-(Cbz) methyl-4,5,6,7-tetrahydrochysene-benzothiazole-3-bromate and
3-carboxymethyl-4-methyl-thiazole-3-bromate,
With and pharmaceutically useful salt or hydrate.
4. pharmaceutical composition, it comprises each described compound of claim 1～3 or its pharmaceutically useful salt or hydrate and at least a pharmaceutically acceptable carrier or vehicle.
5. the method for preparing each described compound of claim 1-3, it comprises makes formula IV compound
Figure A2006100023910003C1
R wherein 1, R 2With the definition of X with claim 1,
Compound reaction with formula V
Figure A2006100023910003C2
Wherein
R 3, Y, Q and R 4Definition with claim 1, X ' is a leavings group, for example F, Cl, Br, I, methanesulfonate are closed or the methylsulphonic acid root are closed,
Obtain compound of Formula I
R wherein 1, R 2, R 3, X, Y, Q, R 4With the definition of Z with claim 1,
Randomly, further hydrolysis R wherein 4The compound of Formula I that is not H obtains formula Ia compound:
Figure A2006100023910004C2
R wherein 1, R 2, R 3, X, Y, the definition of Q and Z is with claim 1,
Randomly, wherein Q be O formula Ia compound again with C 1～C 8The straight or branched alkyl alcohol, C 2～C 8Straight chain or branched-chain alkenyl alcohol, C 3～C 8Cycloalkyl alcohol, aromatic alcohol carries out the condensation dehydration reaction, obtains ester.
Each described compound of claim 1～3 or its pharmaceutically useful salt or hydrate preparation be used for the treatment of or the medicine of prevention and advanced glycation end products (AGEs) diseases associated or symptom in purposes.
7. each described compound has purposes in the medicine of following function in preparation in the claim 1～3: (i) increase skin elasticity or reduce wrinkle of skin, (ii) treat diabetes, the (iii) treatment or the sequela of diabetes-alleviating, (iv) treat or the alleviation kidney injury, (v) treatment or alleviating vascular damage, (vi) treat or alleviation hypertension, (vii) treat or the relieving retina pathology, (viii) treatment or the damage of alleviation crystallin, (ix) treatment or alleviation cataract, (x) treatment or alleviation peripheral neuropathy, (xi) treatment or relief from osteoarthritis.
8. each described compound of claim 1～3 is used to prepare the painted reversal agent of animal body inner teeth gear or other is used to prevent and reverse the purposes of the oral preparations of tooth staining.
9. each described compound of claim 1～3 is used to prevent or reverse the purposes of tooth staining.
10. each described compound of claim 1～3 is used for preparing the purposes of farm crop vegetable-protein or animal proteinum preservation agent.
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WO2010031248A1 (en) * 2008-09-22 2010-03-25 北京摩力克科技有限公司 Thiazolium salt compound and the use of treating the protein aging disease
CN101684106B (en) * 2008-09-22 2013-06-12 北京摩力克科技有限公司 Thiazole onium salt compound and application for treating diseases relative to protein aging thereof
WO2015003625A1 (en) * 2013-07-09 2015-01-15 中国人民解放军军事医学科学院毒物药物研究所 Thiazole inner salt compounds and preparation method and use thereof
CN105377823A (en) * 2013-07-09 2016-03-02 中国人民解放军军事医学科学院毒物药物研究所 Thiazole inner salt compounds and preparation method and use thereof
US11180463B2 (en) 2013-07-09 2021-11-23 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China Thiazole inner salt compounds, and preparation methods and uses thereof

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CA2640396A1 (en) 2007-08-02
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AU2007209704A1 (en) 2007-08-02
JP2009524605A (en) 2009-07-02
CN101007789B (en) 2014-08-20
KR101229282B1 (en) 2013-02-04
US7799813B2 (en) 2010-09-21
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